Valosin-containing protein (VCP) is a member of the AAA+ (ATPases associated with diverse cellular activities) protein family that is involved in many cellular processes including cell cycle regulation, Golgi biogenesis, and the degradation of misfolded proteins1. Its mutation causes inclusion body myopathy, Paget’s disease of bone and frontotemporal dementia (IBMPFD) 2. The IBM is accompanied by muscle fibre degeneration, rimmed vacuole formation and ubiquitin containing sarcoplasmic inclusions. Moreover, muscle fibres of VCPR155H/+ knock-in mice display severely swollen and abnormal mitochondria2; suggesting that they may have impaired energy metabolism. However, no studies have investigated the fatigue resistance of fast and slow muscle fibres isolated from VCP mutant mice. The primary aim of this study was to investigate the fatigue resistance of fast- and slow-twitch muscle fibres isolated from either wild type (WT) or VCP mutant mice. Experiments were performed at 20°C on small bundles of 10-20 muscle fibres dissected from the extensor digitorum longus (EDL, a mainly fast-twitch muscle) and soleus (a mostly slow-twitch muscle) from both VCP mutant and WT mice (cross sectional diameter 340±110μm; n=14). Mice were killed according to the Animals (Scientific Procedures) Act 1986, UK and all the experiments conformed to the local animal welfare committee guidelines. The fibre bundles were mounted horizontally between two stainless steel hooks in a muscle chamber perfused with Ringer’s solution prepared as previously described3. The sarcomere length (SL) was adjusted to 2.5µm and fibre bundle was allowed to equilibrate for ~20 minutes before subjection to the fatigue protocol (FP). During the FP, the fibre bundles were subjected to maximum isometric contractions once every 9 sec (for EDL) or every 4 sec (for soleus). After ~70 contractions, the stimulation rate was reduced to once every 90 sec and the fibre bundles were allowed 15-20min recovery. Only fibre bundles that recovered ≥90% of the force recorded at the start of the FP were included. Our results show that VCP mutation decreased the fatigue resistance of fast-twitch fibres without affecting that of slow-twitch fibres, or the maximum isometric tension (Po). For example, at contraction 60 of the FP, Po declined by 39.6±16% in the fast twitch fibres isolated from the transgenic mice (n=8) but by only 2±8% in WT mice (n=2). The corresponding values in slow-twitch fibres were 9.7±2% and 10±7.6% in the WT (n=2) and transgenic mice (n=2) respectively. Our findings suggest that the effects of VCP mutation in skeletal muscle fibres may be fibre type dependent.